Craniofacial malformations resulting from genetic alterations and/or environmental insults are among the most common forms of human birth defects. Exquisite epithelial-mesenchymal and epithelial- epithelial interactions are critical for growth, patterning, and fusing of the facial prominences/swellings during formation of complex craniofacial structures. Therefore, understanding the underlying molecular mechanisms of these interactions is of paramount importance in understanding facial morphogenesis and pathogenesis. The overall goal of the proposed studies is to identify epithelial signals that regulate facial morphogenesis and ultimately to establish molecular targets of therapeutics for craniofacial anomalies. In contrast to the cranial neural crest-derived mesenchymal cells, which form most facial skeletal structures, relatively little is known about the epithelial contributions to craniofacial morphogenesis. Our preliminary studies demonstrate that epithelial-specific manipulations of the Wnt/ -catenin signaling pathway result in severe facial malformations, including jaw dysmorphism and the cleft lip and/or palate (CL/P). Based on these findings, we hypothesize that the epithelial Wnt/ -catenin signal pathway is the critical inducer of mammalian facial topology. We propose two complementary specific aims to test the hypothesis. First, to uncover the mechanisms by which epithelial -catenin controls mesenchymal cell fate during jaw formation; second, to elucidate the epithelial-specific signaling mechanisms of mammalian middle face morphogenesis. PUBLIC HEALTH RELEVANCE: Craniofacial malformations resulting from genetic alterations and/or environmental insults are among the most common forms of human birth defects. Accordingly, understanding the underlying molecular mechanisms of epithelial signaling is of paramount importance in understanding facial morphogenesis and pathogenesis. The overall goal of the proposed studies is to identify epithelial signals that regulate facial morphogenesis and ultimately to establish molecular targets of therapeutics for craniofacial anomalies.